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High-intensity interval training attenuates post-myocardial infarction remodeling and ITGAM-mediated M4 macrophage
Yaoshan Dun1, Haonan Zhang2, Keyu Gan2
1Division of Cardiac Rehabilitation, Department of Physical Medicine & Rehabilitation, Xiangya Hospital of Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Xiangya Hospital of Central South University, Changsha, Hunan, China; Division of Preventive Cardiology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA; Department of Physical Medicine & Rehabilitation, Xiangya Hospital of Central South University, Jiangxi (National Regional Center for Neurological Diseases), Nanchang, Jiangxi, China.
Background:
While the pro-inflammatory M4 macrophage phenotype contributes to cardiovascular pathogenesis, its specific involvement in chronic post-myocardial infarction (MI) remodeling and responsiveness to different exercise modalities remain unexplored. We hypothesized that high-intensity interval training (HIIT) confers enhanced cardioprotection compared to moderate-intensity continuous training (MICT) by mitigating M4 macrophage polarization.
Methods:
A murine MI model was randomized to 4-week HIIT, MICT, or sedentary groups. Cardiac function, structural remodeling, and macrophage phenotypes were evaluated, followed by transcriptomic profiling of the myocardium. For clinical translation, plasma samples from a human coronary artery disease (CAD) cohort (with/without prior MI) were analyzed. Causality was investigated in vitro using PF4-stimulated human macrophages with targeted genetic knockdown, co-cultured with AC16 ventricular cardiomyocytes.
Results:
Both exercise modalities improved functional capacity and attenuated adverse remodeling post-MI, with HIIT demonstrating enhanced efficacy over MICT. HIIT significantly attenuated MI-induced M4 macrophage polarization, evidenced by diminished expression of MMP7, S100A8, and downstream pro-inflammatory cytokines. Additionally, plasma S100A8 levels were significantly elevated in post-MI patients. Transcriptomic profiling identified integrin subunit alpha M (Itgam) as a critical upstream target; while significantly upregulated post-MI, its expression was effectively suppressed by HIIT. In vitro, targeted ITGAM knockdown effectively suppressed PF4-induced M4 polarization and mitigated macrophage-mediated cardiomyocyte apoptosis.
Conclusions:
Compared to MICT, HIIT demonstrates superior efficacy in attenuating post-MI adverse remodeling, accompanied by significant suppression of pro-inflammatory M4 macrophage polarization. In vitro validations link this protective phenotype to ITGAM downregulation. These findings inform post-MI exercise regimens and highlight potential molecular targets for developing exercise mimetics.
